Mingjie Ma

Renal Denervation Prevents Stroke and Brain Injury via Attenuation of Oxidative Stress in Hypertensive Rats

Background Although renal denervation (RD) is shown to reduce blood pressure significantly in patients with resistant hypertension, the benefit of RD in prevention of stroke is unknown. We hypothesized that RD can prevent the incidence of stroke and brain injury in hypertensive rats beyond blood pressure lowering. Methods and Results High‐salt‐loaded, stroke‐prone, spontaneously hypertensive rats (SHRSP) were divided into 4 groups: (1) control; (2) sham operation; (3) bilateral RD; and (4) hydralazine administration to examine the effect of RD on stroke and brain injury of SHRSP. RD significantly reduced the onset of neurological deficit and death in SHRSP, and this protection against stroke by RD was associated with the increase in cerebral blood flow (CBF), the suppression of blood–brain barrier disruption, the limitation of white matter (WM) lesions, and the attenuation of macrophage infiltration and activated microglia. Furthermore, RD significantly attenuated brain oxidative stress, and NADPH oxidase subunits, P67 and Rac1 in SHRSP. On the other hand, hydralazine, with similar blood pressure lowering to RD, did not significantly suppress the onset of stroke and brain injury in SHRSP. Furthermore, RD prevented cardiac remodeling and vascular endothelial impairment in SHRSP. Conclusions Our present work provided the first experimental evidence that RD can prevent hypertensive stroke and brain injury, beyond blood pressure lowering, thereby highlighting RD as a promising therapeutic strategy for stroke as well as hypertension.

Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation.

This study aimed to examine the potential protective effect of rosuvastatin against cerebral ischemia/reperfusion injury and its mechanisms. Forty-eight male SD rats underwent 90 min of transient middle cerebral artery occlusion (tMCAO), followed by reperfusion. Rats were orally given (1) rosuvastatin 1mg/kg, (2) rosuvastatin 10mg/kg or (3) water (vehicle) once a day from 7 days before to 1 day after induction of tMCAO. Neurological score, infarct volume, and oxidative stress-related molecules (assessed by immunohistochemistry, dihydroethidium staining, or western blotting) were estimated at 24h after reperfusion. Rosuvastatin prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The increases in activated microglia, macrophage, and superoxide levels usually caused by ischemia/reperfusion were significantly ameliorated by rosuvastatin. Rosuvastatin also inhibited the upregulation of gp91(phox) and p22phox, phosphorylation of nuclear factor-kappa B, and induction of cyclooxygenase 2 and inducible nitric oxide synthase, compared with vehicle. The results suggest that pretreatment with rosuvastatin may be a promising therapeutic strategy for cerebral ischemia/reperfusion injury, through attenuation of oxidative stress and inflammation.

ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice

Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density, and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment.

Telmisartan Exerts Sustained Blood Pressure Control and Reduces Blood Pressure Variability in Metabolic Syndrome by Inhibiting Sympathetic Activity

BACKGROUND Accumulating evidence on blood pressure (BP) reduction with various angiotensin II receptor blockers (ARBs) show that the magnitudes and durations of BP control differ across ARBs. However, the mechanism of ARBs is unknown. This work was undertaken to compare telmisartan and valsartan in duration of BP control, BP variability, and effects on the autonomic nervous system. METHODS Using radiotelemetry combined with spectral analysis with a fast Fourier transformation algorithm, we compared the effects of various doses of telmisartan and valsartan on BP and its variability during dark (active phase) and light (inactive phase) periods over 5 weeks in SHR/NDmcr-cp(+/+)(SHRcp) rats, a model of metabolic syndrome. We also compared the effects of these ARBs on autonomic nervous system, central oxidative stress, and inflammation in SHRcp rats. RESULTS Telmisartan exerted a longer-lasting BP-lowering effect and greater attenuation of BP variability in SHRcp than valsartan. Telmisartan decreased low frequency power of systolic BP and increased spontaneous baroreflex gain in SHRcp during both the dark and light periods more than valsartan. Telmisartan reduced 24-hour urinary norepinephrine excretion more than valsartan. Furthermore, telmisartan attenuated oxidative stress and the numbers of gp91(phox)-positive cells and activated microglia and astrocytes in the rostral ventrolateral medulla of SHRcp rats more than valsartan. CONCLUSIONS The superiority of telmisartan over valsartan in sustained BP control and reduction of BP variability was attributed to more suppression of sympathetic activity and more improvement of baroreceptor reflex. The greater suppression of sympathetic activity by telmisartan appeared to be partially mediated by a stronger amelioration of central oxidative stress.

Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer's Disease.

This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimers disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimers disease.